We found that poor oral health status is associated with increased risk of pancreatic cancer. Because poor oral health status is due to oral bacterial dysbiosis, we hypothesize that oral microbiota potentiate pancreas carcinogenesis. Supporting this, recent cohort studies reported that individuals with greater circulating antibodies to multipe oral bacteria have a greater risk of pancreatic cancer. Directly assessing oral microbiome from high-throughput genomic sequencing of oral samples in our recent case-control study, we found that specific gram-negative oral bacteria are associated with 3-fold increased risk of pancreatic cancer. We also showed that these bacteria are present in the human pancreatic duct and showed in animal experiments that oral microbiota access the pancreas and have oncogenic effects via inflammation at the organ site. Because case-control studies are limited for causal inference, a current critical research gap is the lack of prospective confirmation of the link between pre-diagnostic oral microbiome and pancreatic cancer risk. A second research gap is the limited understanding of the comprehensive functional roles of the microbiota and the human host response. The overarching goals of this study are to identify oral microbiota associated with subsequent risk of pancreas cancer and to improve our understanding of the role of the microbiome in host responses potentially related to pancreatic tumorigenesis. Our specific aims are: 1) to test whether oral microbiome is associated with subsequent risk of pancreatic cancer in a nested case-control study and 2) to identify metabolically active bacterial function in the human pancreas and correlate these bacterial activities with expression of human inflammatory signaling pathways. Strengths of this study include a large prospective study design, with oral samples collected prior to cancer development, and state-of-art genomic microbiome and transcriptome assays for assessing oral and pancreas microbiota and related functions. This study is the first study of oral and pancreas microbiome and pancreatic cancer risk. Pancreatic cancer is highly lethal and little is known about ways to detect and prevent this disease. We expect to identify specific oral bacteria associated with risk of pancreas cancer and to identify metabolically active bacterial functions in the pancreas and related host pancreatic inflammatory responses. These outcomes will expand our current limited knowledge on the causes of pancreatic cancer, will help to identify people at high risk for this disease, and may lead to microbial-based prophylactic preventions for pancreatic cancer. Thus, findings may help to rapidly advance our ability to reduce the burden of this highly fatal disease.